ACSS2 (acyl-CoA synthetase short chain family member 2) is a metabolic enzyme that catalyzes the synthesis of acetyl-CoA from acetate and other short-chain fatty acids, playing critical roles in cellular metabolism, gene regulation, and disease pathogenesis 1. Under glucose deprivation, AMPK phosphorylates ACSS2 at S659, promoting its nuclear translocation where it binds transcription factor EB (TFEB) and locally produces acetyl-CoA for histone acetylation at promoters of lysosomal and autophagy genes, supporting tumor cell survival and brain tumorigenesis 1. ACSS2 also functions as a lactyl-CoA synthetase, converting lactate to lactyl-CoA and coupling with KAT2A to promote histone lactylation, leading to expression of oncogenic pathways including Wnt/β-catenin, NF-κB, and PD-L1 for tumor immune evasion 2. In kidney disease, ACSS2 controls de novo lipogenesis in tubular cells, causing NADPH depletion and oxidative stress that triggers NLRP3-dependent pyroptosis and kidney fibrosis 3. Additionally, ACSS2 mediates histone crotonylation to regulate IL-1β expression, promoting macrophage activation and tubular cell senescence in kidney fibrosis 4. The enzyme serves as a metabolic signaling hub connecting nutrient availability to epigenetic regulation and cellular fate decisions across multiple disease contexts.